Aims Endothelial cells regulate vascular tone to control the blood pressure (BP) by producing both relaxing and contracting factors. Previously, we identified methyltransferase-like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, as a key player in alleviating endothelial atherogenic progression. However, its involvement in BP regulation remains unclear. Methods and results To evaluate the role of METTL3 in vivo, mice with EC specific METTL3 deficiency (EC-Mettl3KO) with or without Ang II infusion were used to create a hypertensive model. Functional and MeRIP sequencing analysis were performed to explore the mechanism of METTL3-mediated hypertension. We observed a reduction in endothelial METTL3 activity by Ang II in vitro and in vivo. Endothelial METTL3-deficient mice exhibited higher BP than controls, with no gender disparity observed. The subsequent study primarily conducted in male mice. Through m6A sequencing and functional analysis, we identified m6A modification of various RUNX1 monomers resulted in endothelial dysfunction. Mutations in the 3′UTR region of RUNX1b abolished its luciferase reporter activity, and enhanced eNOS promoter luciferase reporter activity with or without METTL3 overexpression. Overexpression of METTL3 by adeno-associated virus reduced Ang II-induced BP elevation. Conclusion This study reveals that METTL3 alleviates hypertension through m6A-dependent stabilization of RUNX1b mRNA, leading to upregulation of eNOS, thus underscoring the pivotal role of RNA transcriptomics in the regulation of hypertension.

中文翻译：

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METTL3 通过小鼠内皮细胞中的 RUNX1b-eNOS 通路调节血压


目的 内皮细胞通过产生松弛和收缩因子来调节血管张力以控制血压 （BP）。以前，我们确定了甲基转移酶样 3 （METTL3） 是一种初级 N6-甲基腺苷 （m6A） 甲基转移酶，是缓解内皮动脉粥样硬化进展的关键参与者。然而，它参与 BP 调节仍不清楚。方法和结果 为了评估 METTL3 在体内的作用，使用有或没有 Ang II 输注的 EC 特异性 METTL3 缺陷 （EC-Mettl3KO） 小鼠创建高血压模型。进行功能和 MeRIP 测序分析，探讨 METTL3 介导的高血压机制。我们观察到 Ang II 在体外和体内内皮 METTL3 活性降低。内皮 METTL3 缺陷小鼠的血压高于对照组，未观察到性别差异。随后的研究主要在雄性小鼠中进行。通过 m6A 测序和功能分析，我们确定了各种 RUNX1 单体的 m6A 修饰导致内皮功能障碍。RUNX1b 的 3′UTR 区突变消除了其荧光素酶报告基因活性，并增强了 eNOS 启动子荧光素酶报告基因活性，无论是否过表达 METTL3。腺相关病毒过表达 METTL3 降低了 Ang II 诱导的血压升高。结论 本研究揭示了 METTL3 通过 RUNX1b mRNA 的 m6A 依赖性稳定来缓解高血压，导致 eNOS 上调，从而强调了 RNA 转录组学在高血压调控中的关键作用。